Pre-existing anti-viral vector antibodies in gene therapy

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1 Pre-existing anti-viral vector antibodies in gene therapy Impact on assays, study conduct and data interpretation Mark N Milton, Executive Director DMPK-Bx, Novartis AAPS NBC, May 2016

2 Gene Therapy Treatment of diseases caused by mutated genes A normal gene is added to enough somatic cells to restore normal function Viral vectors are commonly used to deliver the gene Viral vectors are derived from, or are, naturally occurring viruses - Adenovirus (e.g. Ad5) - Adeno-associated virus (e.g AAV2, AAV8) - There are over 100 natural AAV variants - AAV7, AAV8, and AAVrh10 were originally isolated from rhesus macaque tissues. 2 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

3 Diseases being treated by gene therapy Blood disorders and anemias Cancer Cardiovascular diseases Congenital blindness and eye diseases Type I diabetes Hemophilia Immunodeficiency diseases Infectious diseases Lysosomal storage disorders Musculoskeletal disorders Neurodegenerative and movement disorders Respiratory disorders 3 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

4 Routes of administration for gene therapies The challenge is to get the as much of the gene therapy as possible into the cells of interest 4 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

5 Challenges for Gene Therapies Immunogenicity The presence of pre-existing anti-viral vector antibodies may result in a sub-optimal, or no, therapeutic response. This is a concern for systemically administered gene therapies but of lesser concern for gene therapies administered into the target tissue Prevalence of pre-existing antibodies can be high There can be an acute reaction to the administration of the gene therapy as a consequence of the activation of the innate immune system However, this response is generally mild and resembles the response to a viral infection Since gene therapies are almost always administered once, the generation of treatment-boosted or treatment-emergent antibodies is of lesser concern 5 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

6 The seroprevalence of anti-viral vector antibodies Some factors that may impact seroprevalence Age Seroprevalence tends to be lower at birth and gradually increases to ~ 3 years of age The impact of age differs for different vectors Health status Incidence may be lower in patients with a compromised immune system compared to healthy volunteers Geographic location Tends to be higher in developing countries - May be due to living conditions, population density, hygienic conditions, different level of health care, MHC background or other factors 6 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

7 Seroprevalence of anti-aav1 antibodies High seroprevalence with regional variability Europe and Israel (N=618) United States (N=934) 7 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

8 Seroprevalence of anti-aav8 antibodies Highly variable between different geographical regions What is important is where the patients have been, not where they are now Population Region Incidence Healthy USA 15.7% Healthy USA Europe Australia 15-20% ~30% 25-30% ~25% Africa Healthy France 38% Healthy China 82% Healthy China 69% Healthy IBD patients Healthy Hemophilia Mucopolysaccharidosis VI (MPS VI) Netherlands 94% 70% Japan 32.9 % 32.9% Turkey 42% Netherlands Italy NOTE: Comparison across studies is fraught with difficulties due to the different assays used by different laboratories 8 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

9 Treatment failure of gene therapies Impact of pre-existing antibodies Diminished hepatocyte transduction in monkeys with preexisting anti-aav8 antibody titers > 1:10 after IV administration of AAV8 vector expressing green fluorescent protein Weak, decaying or no transgene expression in monkeys with pre-existing antibodies when administered AAV2 gene therapy by the intravitreal route Correlation shown between serum and vitreal titers of anti-aav2 antibodies Insufficient efficacy of AAV1 gene therapy administered directly into the human heart 9 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

10 Risk Mitigation Strategies Plasmapheresis Blood is removed and separated into plasma and blood cells. Blood cells are returned to the body, the plasma is disposed and an albumin solution is infused into the patient to replace the plasma volume removed. - May be useful for subjects with low levels of broadly cross-reacting anti-aav antibodies but might be insufficient for patients with high nab titers. Minimizing contact of vector with blood Administer directly into the target organ to avoid exposing the vector to the high levels of Nabs in blood. - Administer into the hepatic artery or portal vein (to target the liver) or intracoronary (to target the heart) or subretinal space (to treat ocular diseases) 10 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

11 Risk Mitigation Strategies Immunosuppression Lower Nab levels by depleting B-cells with drugs such as rituximab - CAVEAT: tolerogenic properties of AAV can be altered and an undesirable immune response to the transgene may be induced Saturation of pre-existing ADA Administration of empty capsids Select serotype to be used as vector based on prevalence of anti-vector antibodies in the intended patient population 11 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

12 Cynomolgus Monkey Serum Anti-AAV8 Antibody Assay Assay Format Sandwich ELISA assay format was used Empty viral capsid (GMP batch) coated on the ELISA plate / colorimetric detection Detected IgM and IgG antibodies Positive Control Commercially-available mouse reagent Negative Control (NC) Use of IgG-depleted serum (a common procedure to remove pre-existing Abs) was not feasible Generation of NC pool from sera with very low signal which was not specific for the viral capsid (i.e signal that was not reduced by addition of excess capsid) 12 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

13 Cynomolgus Monkey Serum Anti-AAV8 Antibody Assay Sample Analysis Screening assay was not performed Samples were directly run in the confirmatory assay Confirmatory cut point could not be established Global precision of the confirmatory assay (n=108) was 24% Any sample with a % inhibition > 24% was reported as positive for anti-aav8 Abs. Samples with % inhibition < 24% and high levels of anti-aav8 antibodies (OD>2) were reanalyzed diluted in the confirmatory assay Samples confirmed positive were analyzed in the titration assay: Two-fold dilution steps were used Only 4 dilutions used in order to maximize throughput 13 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

14 Titer Titer Pre-study anti-aav8 antibodies High incidence that varies between groups Day -20 Day Group 1 Group 2 Group 3 Group 4 Group 5 Unassigned 0 Group 1 Group 2 Group 3 Group 4 Group 5 Unassigned Group 1 Group 2 Group 3 Group 4 Group 5 Unassigned All Day -20 6/8 (75%) 2/2 (100%) 9/10 (90%) 10/10 (100%) 4/10 (40%) 6/6 (100%) 37/46 (80%) Day -13 6/8 (75%) 2/2 (100%) 8/10 (80%) 10/10 (100%) 5/10 (50%) 6/6 (100%) 37/46 (80%) 14 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

15 Titer Change in Titer with time Data from Control Group Antibody titers wax and wane over time in untreated animals Data from control animals can provide information that is useful for the interpretation of data from dosed animals A B C D E F G H Day Day Day Day Day <1 0 Day Day A B C D E F G H Day <1 0 Day Study Week 15 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

16 Cynomolgus Monkey Serum Anti-AAV8 Antibody Assay Learnings Sample analysis Sample analysis timelines will be long (low throughput assay) 89% of the samples were confirmed positive and analyzed in the titer assay (4 dilutions) >150 samples had to be repeated at higher dilutions A calibration-curve based format would have been preferable, especially when a high number of samples have to be analyzed. Use larger dilution steps (e.g. 4x or 8x rather than 2x) Sample with titers > 1024 were not reanalyzed at further dilutions but reported as > 1024 and extrapolated to 2048 for graphical representation. Directly titer the anti-vector antibodies (no screening nor confirmatory assays). Plan for large amounts of reagents Over 80 vials of vg/ml were required for assay development, assay validation and sample analysis Two new pools of NC had to be prepared and qualified during sample analysis Establish plan for data analysis ahead of time Define fold-change in titer to define treatment-emergent ADA Create plan for graphical representation of data 16 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

17 Cynomolgus Monkey Serum Anti-AAV8 Antibody Assay Learnings Study Design and Data Analysis Collect multiple pre-dose samples to better understand prevalence of pre-existing Abs Screen animals prior to study dosing and exclude animals with pre-existing antibodies (dependent upon route of administration) If necessary, consider assigning animals to dose groups based upon their Ab status and titer Utilize the control group to monitor the health of the animals (i.e. use the control group as sentinels for viral infections) Establish plan for data analysis ahead of time Define fold-change in titer to define treatment-emergent ADA Create plan for graphical representation of data 17 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

18 Application to Clinical studies Collect multiple pre-dose samples to better understand prevalence of preexisting Abs Do not simply rely on demographic information Sampling should occur as close to dosing as possible Screen patients prior to study dosing and either exclude patients with preexisting antibodies (dependent upon route of administration) or institute techniques to reduce levels of pre-existing Abs (e.g. plasmapheresis) Consider collecting samples from people in the community in order to monitor the development of anti-viral vector antibodies as a result of a viral infection (sentinel patients) 18 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

19 Acknowledgements Lydia Michaut Tim MacLachlan 19 Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

20 References Calcedo R and Wilson JM (2013). Humoral immune response to AAV. Frontiers in Immunology, 4: 341 Greenberg B, Buler J, Felker GM et al (2016). Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart disease. Gene Therapy, 23: Kotterman MA, Yin L, Strazzeri JM et al (2015). Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to nonhuman primates. Gene Therapy, 22: Monteilhet V, Saheb S, Boutin S et al (2011). A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6 and 8. Molecular Therapy, 19: Wang L, Calcedo R, Bell P et al (2011). Impact of pre-existing immunity on gene transfer to nonhuman primate liver aith adeno-associated virus 8 vectors. Hum Gene Ther, 22: Pre-existing anti-viral vector antibodies in gene therapy Mark N Milton May 2016 AAPS NBC Business Use Only

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